Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma.

Lam, L.T., Wright, G., Davis, R.E., Lenz, G., Farinha, P., Dang, L., Chan, J.W., Rosenwald, A., Gascoyne, R.D., Staudt, L.M.
Journal   Blood
Analytes Measured   STAT3
Matrix Tested   Cell lysates
Year   2008
Volume   111
Page Numbers   3701-13
Application   Phosphoproteins
The activated B cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL) is characterized by constitutive activation of the nuclear factor-kappaB (NF-kappaB) pathway. In this study, we showed that the NF-kappaB pathway induced the expression of the cytokines interleukin (IL)-6 and IL-10 in ABC DLBCL cell lines, which also have high levels of total and phosphorylated signal transducer and activator of transcription (STAT) 3 protein, suggesting autocrine signaling. Using RNA interference for STAT3, we defined a gene expression signature of IL-6 and IL-10 signaling through STAT3. Based on this signature, we constructed a molecular predictor of STAT3 signaling that defined a subset of ABC DLBCL tumors with high expression of STAT3, IL-6, and/or IL-10 and their downstream targets. Although the STAT3-high and STAT3-low subsets had equivalent expression of genes that distinguish ABC DLBCL from germinal center B cell-like DLBCL, STAT3-high ABC DLBCLs had higher expression of signatures that reflected NF-kappaB activity, proliferation, and glycolysis. A small-molecule inhibitor of Janus kinase signaling, which blocked STAT3 signature expression, was toxic only for ABC DLBCL lines and synergized with an inhibitor of NF-kappaB signaling. These findings suggest that the biological interplay between the STAT3 and NF-kappaB pathways may be exploited for the treatments of a subset of ABC DLBCLs.

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